Method for synthesizing pyrazole spiro derivative under catalysis of copper

Abstract

The method comprises the following steps: in an organic solvent system, taking an oxadiazolone compound as shown in a formula (1) and 2-benzylidene-1, 3-indandione as shown in a formula (2) as raw materials, taking a metal copper salt as a catalyst and taking a metal silver salt as a promoter, stirring and reacting at 80 DEG C, tracking and detecting through TLC (Thin Layer Chromatography) until the reaction is complete, filtering, washing and drying to obtain the pyrazole spiro derivative. And performing post-treatment on the reaction liquid to obtain the pyrazole spiro derivative as shown in a formula (3). The method is easy to operate, reagents are easy to obtain, reaction conditions are mild, a reaction system is green and environmentally friendly, products are easy to separate and purify, the yield is high, the method is suitable for synthesizing various highly-functionalized pyrazole spiro derivatives, especially suitable for large-scale industrial production, and the high-purity pyrazole spiro derivatives can be efficiently prepared with high yield. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of fine chemical organic synthesis, and specifically relates to a method for copper-catalyzed synthesis of pyrazole spiro derivatives. Background Art

[0002] Spiro skeletons are commonly present in natural products and functional material molecules. Among them, azaspiro compounds, due to their unique heterocyclic structures, are widely used in materials science, agrochemistry, and medicinal chemistry. For example, fluspirilene is a spiro antipsychotic drug discovered by Janssen Pharmaceutical Research and has been approved for the treatment of schizophrenia since 1970; spiropidion is the fourth spirotetronic acid insecticide developed by Syngenta, which has a broad-spectrum insecticidal effect and shows excellent control effects against sucking mouthpart pests and some resistant pests; trilaciclib is a spiro inhibitor of cyclin-dependent kinases and is used in cancer patients receiving certain types of chemotherapy to protect the bone marrow from chemotherapy-induced damage. Therefore, exploring different methods to synthesize diverse azaspiro compounds is a hot topic in organic synthesis research, with broad prospects and great significance.

[0003]

[0004] Currently, the existing methods for synthesizing spiro compounds still have some defects, such as narrow substrate scope, harsh reaction conditions, low product yield, lack of practical value, etc. Therefore, it is of great significance to develop and find a new and practical method for synthesizing spiro compounds. Summary of the Invention

[0005] The purpose of the present invention is to provide a method for copper-catalyzed synthesis of pyrazole spiro derivatives, which has simple operation, easily available reagents, mild reaction conditions, and high product yield.

[0006] To achieve the above purpose, the technical solution adopted by the present invention is as follows: A method for copper-catalyzed synthesis of pyrazole spiro derivatives, in an organic solvent system, using the oxadiazolone compound shown in formula (1) and 2-benzylidene-1,3-indanedione shown in formula (2) as raw materials, using metal copper salt as a catalyst and metal silver salt as a co-catalyst, stirring and reacting at 80 °C, detecting by TLC until the reaction is complete, and obtaining the pyrazole spiro derivative shown in formula (3) after post-treatment of the reaction solution;

[0007] Wherein, the organic solvent is one of toluene, 1,2-dichloroethane, acetonitrile, dichloromethane, dimethyl sulfoxide;

[0008] The metal copper salt is one of cuprous iodide, cuprous bromide, cuprous oxide, copper oxide;

[0009] The metal silver salt is one of silver carbonate, silver bromide, and silver oxide;

[0010] The molar ratio between the oxadiazolone compound and 2-benzylidene-1,3-indanedione is 2:1;

[0011]

[0012] In the formula, R 1 is -Cl or -Br; R 2 is -H or -CH 3 ; R 3 is -H, -CH 3 , -Br, -OCH 3 in one of them; R 4 is -H, -CH 3 , -Cl, -Br in one of them.

[0013] Preferably, the metal copper salt is cuprous iodide, and the metal silver salt is silver carbonate.

[0014] Preferably, the dosage of the metal copper salt is 10 mol% of the oxadiazolone compound shown in formula (1), and the dosage of the metal silver salt is 10 mol% of the oxadiazolone compound shown in formula (1).

[0015] Preferably, the organic solvent is toluene.

[0016] Preferably, the dosage of the organic solvent is 5 mL / mmol based on the amount of substance of the oxadiazolone compound shown in formula (1).

[0017] Preferably, the developing agent used for TLC to track the reaction is petroleum ether:ethyl acetate = 10:1, V / V.

[0018] Furthermore, the method for post-treatment of the reaction solution is as follows: after the reaction is completed, the reaction is quenched with water, extracted with ethyl acetate, then the organic phase is washed with water, dried over anhydrous sodium sulfate, distilled under reduced pressure, and then separated by silica gel column chromatography. The obtained eluate is distilled under reduced pressure and dried to obtain the pyrazolo spiro derivative shown in formula (3).

[0019] Preferably, the eluate for silica gel column chromatography is petroleum ether:ethyl acetate = 10:1, V / V.

[0020] Compared with the prior art, the present invention has the following beneficial effects:

[0021] In the present invention, metal copper salt is selected as the catalyst, and oxadiazolone compounds and 2-benzylidene-1,3-indanedione are used as raw materials to synthesize pyrazolo-spiro derivatives by a one-pot method of decarboxylation rearrangement; the operation of the present invention is simple, the reagents are easily available, the reaction conditions are mild, the reaction system is green and environmentally friendly, the product is easy to separate and purify, and the yield is high. It is suitable for the synthesis of various highly functionalized pyrazolo-spiro derivatives, especially suitable for large-scale industrial production, and can obtain high-purity pyrazolo-spiro derivatives with high efficiency and high yield. Description of the Drawings

[0022] Figure 1 1H-NMR nuclear magnetic resonance spectrum of the pyrazolo-spiro derivative 3a prepared in Example 1; 1 1H-NMR nuclear magnetic resonance spectrum;

[0023] Figure 2 13C-NMR nuclear magnetic resonance spectrum of the pyrazolo-spiro derivative 3a prepared in Example 1; 13 13C-NMR nuclear magnetic resonance spectrum;

[0024] Figure 3 1H-NMR nuclear magnetic resonance spectrum of the pyrazolo-spiro derivative 3b prepared in Example 2; 1 1H-NMR nuclear magnetic resonance spectrum;

[0025] Figure 4 13C-NMR nuclear magnetic resonance spectrum of the pyrazolo-spiro derivative 3b prepared in Example 2; 13 13C-NMR nuclear magnetic resonance spectrum;

[0026] Figure 5 1H-NMR nuclear magnetic resonance spectrum of the pyrazolo-spiro derivative 3c prepared in Example 3; 1 1H-NMR nuclear magnetic resonance spectrum;

[0027] Figure 6 13C-NMR nuclear magnetic resonance spectrum of the pyrazolo-spiro derivative 3c prepared in Example 3; 13 13C-NMR nuclear magnetic resonance spectrum;

[0028] Figure 7 1H-NMR nuclear magnetic resonance spectrum of the pyrazolo-spiro derivative 3d prepared in Example 4; 1 1H-NMR nuclear magnetic resonance spectrum;

[0029] Figure 8 13C-NMR nuclear magnetic resonance spectrum of the pyrazolo-spiro derivative 3d prepared in Example 4; 13 13C-NMR nuclear magnetic resonance spectrum;

[0030] Figure 9 1H-NMR nuclear magnetic resonance spectrum of the pyrazolo-spiro derivative 3e prepared in Example 5; 1 1H-NMR nuclear magnetic resonance spectrum;

[0031] Figure 10 13C-NMR nuclear magnetic resonance spectrum of the pyrazolo-spiro derivative 3e prepared in Example 5; 13 13C-NMR nuclear magnetic resonance spectrum;

[0032] Figure 11 1H-NMR of the pyrazolospiro derivative 3f prepared in Example 6 1 1H-NMR nuclear magnetic resonance spectrum;

[0033] Figure 12 1H-NMR of the pyrazolospiro derivative 3f prepared in Example 6 13 13C-NMR nuclear magnetic resonance spectrum

[0034] Figure 13 1H-NMR of the pyrazolospiro derivative 3g prepared in Example 7 1 1H-NMR nuclear magnetic resonance spectrum;

[0035] Figure 14 1H-NMR of the pyrazolospiro derivative 3g prepared in Example 7 13 13C-NMR nuclear magnetic resonance spectrum;

[0036] Figure 15 1H-NMR of the pyrazolospiro derivative 3h prepared in Example 8 1 1H-NMR nuclear magnetic resonance spectrum;

[0037] Figure 16 1H-NMR of the pyrazolospiro derivative 3h prepared in Example 8 13 13C-NMR nuclear magnetic resonance spectrum. Detailed implementation manners

[0038] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments.

[0039] Example 1: Preparation of pyrazolospiro derivative 3a

[0040]

[0041] Add 4-(4-chlorophenyl)-2-phenyl-3-(o-tolyl)-1,2,4-oxadiazol-5-one 1a (146 mg, 0.4 mmol), copper(I) iodide (7 mg, 10 mmol%), silver carbonate (11 mg, 10 mmol%), toluene (2 mL) into a 10 mL Schlenk flask equipped with a magnetic stirring device. Finally, add 2-(4-methylbenzylidene)-1H-indene-1,3(2H)-dione 2a (50 mg, 0.2 mmol). After stirring evenly, place it in an 80 °C oil bath and continue stirring. TLC (the developing solvent is V 石油醚 :V 乙酸乙酯= 10:1) The detection substrate disappeared, and the reaction ended. The reaction solution was poured into water (30 mL), extracted with ethyl acetate (3 × 10 mL), and the organic phases were combined. Then the organic phase was backwashed with water (3 × 10 mL), dried over anhydrous sodium sulfate, filtered by suction, and distilled under reduced pressure to obtain a viscous solid. Finally, through silica gel column chromatography (the eluent was V 石油醚 :V 乙酸乙酯 = 10:1) for separation. The obtained eluent was distilled under reduced pressure and dried to obtain a white solid, which was confirmed to be pyrazolospiro derivative 3a by NMR and MS, and its yield was 91%.

[0042] The hydrogen spectrum and carbon spectrum are as shown in Figure 1 and Figure 2 . The spectral analysis data are as follows for 3a:

[0043] Yellow solid; 1 H NMR (400 MHz, Chloroform-d): δ H 7.79 - 7.77 (m, 1H), 7.73 - 7.62 (m, 3H), 7.36 - 7.3 (m, 4H), 7.20 - 7.19 (m, 3H), 7.15 - 7.13 (m, 3H), 7.08 - 7.05 (m, 1H), 7.02 - 6.99 (m, 3H), 6.96 - 6.94 (m, 2H), 6.73 - 6.71 (m, 2H), 5.64 (s, 1H), 5.49 (s, 1H), 2.20 (s, 3H), 1.84 (s, 3H)( Figure 1 ); 13 C NMR (101 MHz, Chloroform-d): δ C 198.0, 195.7, 150.6, 148.1, 142.2, 141.1, 138.0, 136.3, 135.9, 135.8, 133.5, 133.0 131.6, 130.3, 129.5, 128.9, 128.4, 128.1, 126.9, 126.7, 123.6, 123.0, 120.7, 117.4, 114.9, 112.8, 72.7, 71.8, 69.4, 21.1, 19.7( Figure 2 ); HRMS (ESI-TOF, m / z): calcd for C 37 H 30 ClN 2 O [M + H] + , 569.1996; found, 569.1999.

[0044] Example 2:

[0045] Replace 2a in Example 1 with 2b, and keep other conditions the same as in Example 1. The yield is 96%.

[0046]

[0047] The hydrogen NMR and carbon NMR spectra are as shown in Figure 3 and Figure 4 shown below. The spectral analysis data are as follows for 3b:

[0048] Yellow solid; 1 H NMR (400 MHz, Chloroform-d): δ H 7.68 (m, 3H), 7.64 (m, 2H), 7.29–7.26 (m, 2H), 7.23–7.21 (m, 2H), 7.15–7.08 (m, 5H), 6.99–6.96 (m, 3H), 6.83–6.80 (m, 4H), 6.61 (d, J = 6.4 Hz, 1H), 5.76 (s, 1H), 5.71 (s, 1H), 1.98 (s, 3H), 1.96 (s, 3H) ( Figure 3 ); 13 C NMR (101 MHz, Chloroform-d): δ C 197.5, 196.9, 149.6, 148.7, 141.6, 141.4, 136.0, 135.3, 135.2, 134.1, 134.0, 130.5, 130.4, 129.2, 129.1, 129.0, 128.8, 128.0, 127.9, 126.7, 126.6, 125.2, 123.1, 123.0, 120.6, 116.2, 115.0, 112.8, 71.1, 71.0, 68.6, 19.7 ( Figure 4 ); HRMS (ESI-TOF, m / z): calcd for C 37 H 30 ClN 2 O 2 [M+H] + , 569.1996; found, 569.1997.

[0049] Example 3:

[0050] Replace 2a in Example 1 with 3b, and keep other conditions the same as in Example 1. The yield is 94%.

[0051]

[0052] The hydrogen NMR and carbon NMR spectra are as shown in Figure 5 and Figure 6 shown below. The spectral analysis data are as follows for 3c:

[0053] Yellow solid; 1 H NMR(400MHz,Chloroform-d):δ H 7.80 - 7.66(m,4H),7.37 - 7.11(m,12H),7.07–7.06(m,1H),7.01 - 6.98(m,3H),6.69(d,J=6.8Hz,2H),5.65(s,1H),5.49(s,1H),1.87(s,3H)( Figure 5 ); 13 C NMR(101MHz,Chloroform-d):δ C 197.7,195.3,150.5,147.4,142.3,141.0,136.2,135.5,133.5,132.0,130.4,129.0,128.8,128.4,128.2,126.8,125.7,123.8,123.1,122.3,120.9,116.7,114.9,72.0,69.3,19.7( Figure 6 );HRMS(ESI-TOF,m / z):calcd for C 36 H 27 ClBrN 2 O 2 [M + H] + ,633.0944;found,633.0946.

[0054] Example 4:

[0055] Using 2d to replace 2a in Example 1, with other conditions the same as in Example 1, the yield is 90%.

[0056]

[0057] The hydrogen spectrum and carbon spectrum are as shown in Figure 7 and Figure 8 , and the spectral analysis data are as follows for 3d:

[0058] Yellow solid; 11 H NMR(400MHz,Chloroform-d):δ H7.81 - 7.80(m, 1H), 7.76 - 7.69(m, 2H), 7.68–7.66(m, 1H), 7.43(s, 1H), 7.37 - 7.26(m, 5H), 7.22 - 7.11(m, 4H), 7.07 - 7.03(m, 2H), 7.01 - 6.99(m, 3H), 6.71(d, J=8.8Hz, 2H), 5.65(s, 1H), 5.47(s, 1H), 1.89(s, 3H)( Figure 7 ); 13 C NMR(101MHz, Chloroform - d): δ C 197.4, 195.3, 150.5, 147.4, 142.1, 141.0, 138.8, 136.2, 136.1, 136.0 133.5, 131.6, 130.4, 129.0, 128.8, 128.4, 128.2, 126.8, 126.0, 125.7, 123.8, 123.2, 122.8, 120.9, 116.9, 114.9, 72.1, 71.9, 69.4, 29.7, 19.7( Figure 8 );HRMS(ESI - TOF, m / z): calcd for C 36 H 27 ClBrN 2 O 2 [M + H] + , 633.0944;found, 633.0948.

[0059] Example 5:

[0060] Using 2e to replace 2a in Example 1, with other conditions the same as in Example 1, the yield is 76%.

[0061]

[0062] The hydrogen spectrum and carbon spectrum are as shown in Figure 9 and Figure 10 , and the spectral analysis data are as follows for 3e:

[0063] White solid; 1 H NMR(400MHz, Chloroform - d): δ H7.79 - 7.77 (m, 1H), 7.72 - 7.62 (m, 4H), 7.36–7.32 (m, 3H), 7.22 - 7.13 (m, 5H), 7.22 - 7.11 (m, 4H), 7.07 - 6.90 (m, 8H), 6.77 - 6.72 (m, 2H), 5.64 (s, 1H), 5.46 (s, 1H), 2.10 (s, 3H), 2.05 (s, 3H), 1.89 (s, 3H)( Figure 9 ); 13 C NMR (101 MHz, Chloroform - d): δ C 197.9, 195.8, 150.7, 147.8, 142.3, 141.2, 138.9, 136.6, 136.4, 135.8, 135.7, 133.5, 133.4, 130.3, 130.0, 128.9, 128.6, 128.5, 128.1, 128.0, 126.7, 125.2, 124.6, 123.5, 123.0, 120.7, 116.9, 115.0, 72.9, 71.8, 69.4, 19.8, 19.7, 19.4( Figure 10 ); HRMS (ESI - TOF, m / z): calcd for C 21 H 19 ClNO 5 [M + H] + , 400.0946; found, 401.0958.

[0064] Example 6:

[0065] Using 2f to replace 2a in Example 1, with other conditions the same as in Example 1, the yield is 82%.

[0066]

[0067] The hydrogen spectrum and carbon spectrum are as shown in Figure 11 and Figure 12 as follows. The spectral analysis data for 3f are as follows:

[0068] Yellow solid; 1 H NMR (400 MHz, Chloroform - d): δ H 7.79–7.63 (m, 4H), 7.35–7.27 (m, 3H), 7.22–6.97 (m, 9H), 6.92–6.88 (m, 2H), 6.77–6.73 (m, 2H), 6.69–6.67 (m, 1H), 5.66 (s, 1H), 5.48 (s, 1H), 3.57 (s, 3H), 1.90 (s, 3H)(Figure 11 ); 13 CNMR(101MHz, Chloroform-d) δ C 197.7, 195.8, 159.7, 150.6, 147.7, 142.3, 141.5, 137.6, 136.2, 136.0, 135.5, 133.6, 130.3, 129.8, 128.9, 128.7, 128.5, 128.1, 126.7, 125.4, 123.6, 123.0, 120.7, 119.3, 116.8, 116.1, 115.7, 114.9, 114.4, 112.6, 73.1, 71.7, 69.4, 59.7, 56.5, 55.0, 29.3, 19.7( Figure 12 ); HRMS(ESI-TOF, m / z): calcd for C 37 H 30 ClN 2 O 3 [M + H] + , 585.1945; found, 585.1949.

[0069] Example 7:

[0070] Using 2 g to replace 2a in Example 1, with other conditions the same as in Example 1, the yield is 85%.

[0071]

[0072] The hydrogen spectrum and carbon spectrum are as shown in Figure 13 and Figure 14 shown below. The spectral analysis data are as follows for 3g:

[0073] Yellow oil; 1 H NMR(400 MHz, Chloroform-d): δ H 7.81–7.79(m, 1H), 7.74–7.71(m, 2H), 7.67–7.65(m, 1H), 7.37–7.33(m, 1H), 7.30–7.25(m, 4H), 7.23–7.19(m, 2H), 7.17–7.06(m, 5H), 7.01–6.96(m, 3H), 6.74–6.68(m, 2H), 5.65(s, 1H), 5.50(s, 1H), 1.87(s, 3H)( Figure 13 ); 13 C NMR(101 MHz, Chloroform-d) δ C198.2, 197.7, 195.4, 195.1, 150.5, 149.6, 148.4, 147.4, 142.3, 142.2, 140.9, 140.8, 136.2, 136.1, 136.0, 135.9, 135.0, 134.9, 134.1, 134.0, 133.5, 133.4, 130.4, 130.3, 129.1, 129.0, 129.0, 128.9, 128.9, 128.7, 128.5, 128.4, 128.4, 128.3, 128.2, 126.7, 125.7, 125.5, 123.7, 123.1, 120.9, 120.8, 116.9, 116.2, 116.1, 115.7, 114.9, 72.0, 71.9, 69.3, 69.3, 19.7( Figure 14 ); HRMS(ESI-TOF, m / z): calcd for C 36 H 27 Cl 2 N 2 O 2 [M + H] + , 589.1450; found, 589.1452.

[0074] Example 8:

[0075] Using 1b to replace 1a in Example 1, with other conditions the same as in Example 1, the yield is 92%.

[0076]

[0077] The hydrogen spectrum and carbon spectrum are as shown in Figure 15 and Figure 16 as follows. The spectral analysis data for 3h are as follows:

[0078] Yellow oil; 1 H NMR(400 MHz, Chloroform-d): δ H 7.80–7.78(m, 1H), 7.74–7.63(m, 3H), 7.42(d, J = 8.4 Hz, 2H), 7.31(d, J = 7.6 Hz, 1H), 7.22–7.18(m, 5H), 7.12–7.06(m, 2H), 6.95–6.91(m, 5H), 6.76(d, J = 8.0 Hz, 2H), 5.56(s, 1H), 5.53(s, 1H), 2.20(s, 3H), 1.87(s, 3H)( Figure 15 ); 13 C NMR(101 MHz, Chloroform-d) δ C198.5, 195.4, 150.3, 148.7, 142.3, 141.0, 137.9, 136.2, 135.94, 135.87, 133.4, 133.1, 131.7, 130.2, 129.4, 128.8, 128.5, 128.1, 126.9, 126.7, 123.5, 123.0, 120.5, 116.7, 115.7, 112.7, 72.8, 71.9, 69.4, 21.1, 19.7( Figure 16 ); HRMS (ESI-TOF, m / z): calcd for C 37 H 30 BrN 2 O 2 [M + H] + , 613.1491; found, 613.1496.

Claims

1. A method for synthesizing pyrazole spiro derivatives by copper catalysis, characterized in that: In an organic solvent system, an oxadiazolone compound represented by formula (1) and 2-benzylidene-1,3-indanedione represented by formula (2) are used as raw materials, a metal copper salt is used as a catalyst, and a metal silver salt is used as a co-catalyst. The reaction is stirred at 80° C., and TLC tracking is performed until the reaction is complete. After the reaction solution is treated, a pyrazole spiro derivative represented by formula (3) is obtained; Wherein, the organic solvent is one of toluene, 1,2-dichloroethane, acetonitrile, dichloromethane, and dimethyl sulfoxide; The metal copper salt is one of cuprous iodide, cuprous bromide, cuprous oxide, and cupric oxide; The metal silver salt is one of silver carbonate, silver bromide and silver oxide; The molar ratio between the oxadiazolone compound and 2-benzylidene-1,3-indanedione is 2:1; In the formula, R 1 is -Cl or -Br; R 2 is -H or -CH3; R 3 is one of -H, -CH3, -Br, -OCH3; R 4 It is one of -H, -CH3, -Cl, and -Br.

2. The method for synthesizing pyrazole spiro derivatives by copper catalysis according to claim 1, characterized in that: The metal copper salt is cuprous iodide, and the metal silver salt is silver carbonate.

3. The method for synthesizing pyrazole spiro derivatives by copper catalysis according to claim 1 or 2, characterized in that: The amount of the metal copper salt used is 10 mol% of the oxadiazolone compound represented by formula (1), and the amount of the metal silver salt used is 10 mol% of the oxadiazolone compound represented by formula (1).

4. The method for synthesizing pyrazole spiro derivatives by copper catalysis according to claim 1 or 2, characterized in that: The organic solvent is toluene.

5. The method for synthesizing pyrazole spiro derivatives by copper catalysis according to claim 1 or 2, characterized in that: The amount of the organic solvent used is 5 mL / mmol based on the amount of the oxadiazolone compound represented by formula (1).

6. The method for synthesizing pyrazole spiro derivatives by copper catalysis according to claim 1 or 2, characterized in that: The developing solvent used for TLC tracking of the reaction was petroleum ether:ethyl acetate = 10:1, V / V.

7. The method for synthesizing pyrazole spiro derivatives by copper catalysis according to claim 1 or 2, characterized in that: The reaction solution treatment method is as follows: after the reaction is completed, the reaction is quenched with water, extracted with ethyl acetate, and then the organic phase is backwashed with water, dried over anhydrous sodium sulfate, distilled under reduced pressure, and then separated by silica gel column chromatography, and the obtained eluate is distilled under reduced pressure and dried to obtain the pyrazole spiro derivative shown in formula (3).

8. The method for synthesizing pyrazole spiro derivatives by copper catalysis according to claim 7, characterized in that: The eluent of the silica gel column chromatography was petroleum ether:ethyl acetate=10:1, V / V.

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